Refractory Patients Research Articles

A retrospective budget impact analysis of fidaxomicin treatment for Clostridioides difficile infections (CDI) in Germany

ABSTRACT Background Clostridioides difficile is the most common cause of healthcare-associated diarrhea. Research suggests that treating C. difficile infections (CDI) with fidaxomicin (FDX) is more effective than vancomycin (VAN), with potential cost savings. The objective was to calculate the budget impact of FDX treatment compared to VAN from a German payer perspective. Research design and methods The analysis used real-world data of patients discharged from University Hospital Cologne between Jan-01–2018 and Dec-31–2019. We identified recurrent and non-recurrent CDI cases and calculated direct treatment costs based on G-DRG flat rates. To calculate average costs per treatment and the budget impact, recurrence probabilities for VAN and FDX were taken from published evidence (28-day and 90-day scenarios). Results Totally, 475 cases were analyzed, thereof 421 non-recurrent, causing mean costs of €32,901 per case (95% CI: 27.752–38.050). Thirty-two patients experienced a recurrence within 28 days, yielding mean costs of €10,952 (95% CI: 5.627–16.277) for their additional hospital stay. The resulting budget impact was €1,303 (95% CI: 670–1.937) in favor of FDX, ranging from €148.34 to €2,190.30 in scenario analyses. Conclusion The analysis indicates FDX treatment can lead to cost savings compared to VAN. Future research should focus on specific patient groups, such as refractory CDI patients.

Prevalence of omalizumab resistant chronic urticaria and real world effectiveness of dupilumab in omalizumab refractory chronic urticaria patients: a single center experience.

Chronic urticaria (CU) is characterized by wheals, angioedema, or both lasting for ≥ 6 weeks with chronic spontaneous urticaria (CSU) being the most common subtype. Omalizumab-resistant CSU cases represent an unmet clinical need. In this study, we aimed to assess the prevalence and predictors of omalizumab failure in a large cohort of CU patients and assess the effectiveness of dupilumab for omalizumab-recalcitrant CU. Of 338 CU patients, 33 received omalizumab. 69.7% (23 patients) were responders and 30.3% (10 patients) non-responders. Bivariate regression demonstrated that female sex (adjusted OR [aOR] = 1.53; 95%CI = 1.14-2.06), higher baseline UAS7 (aOR = 1.05; 95%CI = 1.01-1.09) and older age (controlling for sex) (aOR = 1.00; 95%CI = 1.00, 1.01) were associated with omalizumab failure. Of 10 omalizumab-refractory patients, three were well controlled with cyclosporine (all children), whereas the seven adults failed on average 5.6 ± 2.6 therapies including cyclosporine. All 7 achieved a complete response with dupilumab with time to response varying between 1 to 6 months. While our results suggest a favourable efficacy of dupilumab omalizumab-resistant cases, future confirmatory studies are required.

Fluorine-18 fluorodeoxyglucose uptake change in liver, mediastinal blood pool, and lymphoid cell-rich organs during programmed cell death-1 immunotherapy in lymphoma.

The aim of this study was to evaluate metabolism change in reference organs (liver and mediastinum) and lymphoid cell-rich organs (spleen and bone marrow) during programmed cell death-1 immunotherapy in relapsed or refractory lymphoma patients. A total of 66 patients with baseline and serial monitoring fluorodeoxyglucose (FDG) PET/computed tomography scans were retrospectively enrolled. Mean standardized uptake value (SUV) and maximum SUV of evaluated organs were obtained by two reviewers, and their association with tumor burden and clinical response were evaluated. Immune-related adverse events detected by FDG PET/computed tomography were also recorded. The SUV values of reference organs and lymphoid cell-rich organs did not change significantly during the immunotherapy process. The intersubject variability of these values ranged from 13.0 to 28.5%. Meanwhile, metabolism of reference organs was affected by neither the tumor burden nor clinical response. SUV change of lymphoid cell-rich organs was associated with clinical response to immunotherapy. Responders showed decreased metabolism, while nonresponders showed a reverse trend (spleen SUVmaximum: -0.30 ± 0.47 vs. 0.18 ± 0.39, P = 0.001, spleen SUVmean: -0.24 ± 0.39 vs. 0.14 ± 0.31, P = 0.001; and bone marrow SUVmaximum: -0.14 ± 0.37 vs. 0.07 ± 0.46, P = 0.042, respectively). The influence of immune-related adverse events on the SUV change in evaluated organs was NS. During programmed cell death-1 immunotherapy, metabolism change of reference organs is influenced neither by tumor burden nor by clinical response, while FDG uptake change of lymphoid cell-rich organs is significantly associated with clinical response.

Metabolomic screening of radioiodine refractory thyroid cancer patients and the underlying chemical mechanism of iodine resistance

Radioiodine refractory (RAIR) patients do not benefit from iodine-131 therapy. Thus, timely identification of RAIR patients is critical for avoiding ineffective radioactive iodine therapy. In addition, determining the causes of iodine resistance will facilitate the development of novel treatment strategies. This study was comprised of 20 RAIR and 14 non-radioiodine refractory (non-RAIR) thyroid cancer patients. Liquid chromatography-mass spectrometry was used to identify differences in the serum metabolites of RAIR and non-RAIR patients. In addition, chemical assays were performed to determine the effects of the differential metabolites on iodine uptake. Metabolic pathway enrichment analysis of the differential metabolites revealed significant differences in the phenylalanine and tyrosine metabolic pathways. Notably, quinate and shikimic acid, metabolites of the tyrosine pathway, were significantly increased in the RAIR group. In contrast, the phenylalanine pathway metabolites, hippuric acid and 2-phenylacetamide, were markedly decreased in the RAIR group. Thyroid peroxidase plays an important role in catalyzing the iodination of tyrosine residues, while the ionic state of iodine promotes the iodination reaction. Quinate, shikimic acid, hippuric acid, and 2-phenylacetamide were found to be involved in the iodination of tyrosine, which is a key step in thyroid hormone synthesis. Specifically, quinate and shikimic acid were found to inhibit iodination, while hippuric acid and 2-phenylacetamide promoted iodination. Abnormalities in phenylalanine and tyrosine metabolic pathways are closely associated with iodine resistance. Tyrosine is required for thyroid hormone synthesis and could be a potential cause of iodine resistance.

A Simulation-Based Assessment of Levetiracetam Concentrations Following Fixed and Weight-Based Loading Doses: A Meta-Regression and Pharmacokinetic Modeling Analysis.

Current recommendations for refractory status epilepticus (SE) unresponsive to benzodiazepines suggest a loading dose of levetiracetam (LEV) of 60 mg/kg to a maximum of 4500 mg. LEV therapeutic drug monitoring can help guide therapy and is garnering increasing attention. The objective of this study is to simulate the probability of target attainment (PTA) of fixed dose and weight-based loading doses of LEV with respect to established therapeutic target concentrations. Meta-regression of the current literature was performed to evaluate the relationship between intravenous LEV loading dose and seizure cessation in refractory SE patients. A previously published pharmacokinetic model was used to simulate the PTA capacity of competing single intravenous dosing schemes (fixed vs weight-based dosing) to achieve maximum (Cpeak) and 12-h (C12h) plasma concentrations that exceed 12 mg/L. The meta-regression indicated that dosage was not a statistically significant modulator of seizure control at dosages between 20 and 60 mg/kg. Stochastic simulations showed all dosing schemes achieved plasma Cpeak >12 mg/L, but C12h levels were <12 mg/L in subjects over 60 kg with a fixed dose ≤2000 mg or in subjects <60 kg with a weight-based dose <30 mg/kg. Dosages of 40 and 60 mg/kg provided ≥90% PTAs across all weights. Using a weight-based loading dose of 40 mg/kg, up to a suggested maximum of 4500 mg, improves the likelihood of achieving a sustained therapeutic drug concentration after the initial LEV dose, whereas fixed <3000 mg may not achieve the desired concentration before maintenance dosing.

Would hyperbaric oxygen therapy be a supportive treatment method for refractory idiopathic granulomatous mastitis?

BackgroundRefractory IGM causes patients to use antibiotics, steroid therapy, immunosuppressive agents for a very long time and even leads to surgical procedures resulting in the loss of breast tissue. Hyperbaric Oxygen Therapy (HBOT) is a frequently used method in the treatment of wounds that are difficult to heal. We thought that HBOT would be an alternative treatment method for refractory IGM patients. MethodsIt is a retrospective cohort study on refractory IGM patients conducted at three tertiary care treatment centers between January 2021 and July 2023. The patients were evaluated in two groups: those who only took steroid treatment and those who received HBOT and steroid treatment. The demographic and clinical characteristics of the patients, the types of treatment applied and their responses to treatment were evaluated. ResultsThere were no significant differences generally in the demographic and clinical features in both groups. The incidence of multicentric GM was found to be higher in the HBOT group (66.67%; p = 0.044). Although the recovery results were similar in both groups, the average daily steroid dose and duration of drug use were found to be higher in the group receiving only steroid treatment (16 mg vs. 4 mg and 270 days vs. 30 days) (p<0.001). ConclusionIn our study, we showed for the first time in the literature that HBOT is effective in the treatment of refractory IGM patients. Our study needs to be supported by prospective studies evaluating cost effectiveness and possible long term complications..

Oral decitabine/cedazuridine is an effective ambulatory therapy for patients with myelofibrosis refractory to JAK2 inhibitor therapy

MicroabstractPatients with myelofibrosis (MF) who are refractory to JAK2 inhibitors (JAKi) and/or have increasing blast cell numbers have dismal prognosis. We studied a novel ambulatory regimen of decitabine-cedazuridine (DEC-C) +/- JAKi therapy in patients with high-risk MF who were refractory to prior JAKi or MPN-accelerated phase. We demonstrate the therapeutic benefit of this strategy as evidenced by reduction or stabilization of blast cell counts, decrease in splenomegaly or successful bridge to stem-cell transplant. Myelosuppression is a common adverse event but treatment length reduction from 5 to 3 days of DEC-C/cycle is feasible and reduces toxicity without comprising the efficacy. BackgroundOutcomes are dismal for patients with myelofibrosis (MF) who are no longer responsive to JAK2 inhibitors (JAKi) and/or have increasing blast cell numbers. Although prior reports have suggested the benefits of intravenous decitabine (DAC) combined with ruxolitinib for patients with Myeloproliferative Neoplasm (MPN) accelerated/blast phase (AP/BP), decitabine-cedazuridine (DEC-C), an oral fixed-dose combination providing equivalent pharmacokinetic exposure, has not been evaluated in MF. MethodsWe conducted a retrospective analysis of 14 patients with high-risk MF refractory to ruxolitinib or MPN-AP (10-19% blasts) treated with DEC-C +/- JAKi at Mount Sinai Hospital from 2021-2024. ResultsThe cohort was elderly (median age,76 years) and almost uniformly possessed high risk mutations with 13 of the 14 patients progressing on JAKi therapy. With a median follow-up of 9.4 months, the median overall survival (OS) was 29 months for the entire cohort. Median OS was 10.8 months for MPN-AP and was not reached for ruxolitinib refractory MF patients. All patients (N=9) receiving >4 cycles of DEC-C had clinical benefit exemplified by a reduction in blast cell numbers, spleen size, and lack of progression to MPN-BP (78%). Furthermore, 3/14 patients proceeded to allogeneic stem cell transplant. Myelosuppression was a common adverse event which was managed by reducing the number of days of administration of DEC-C from 5 to 3. ConclusionsThis report demonstrates the feasibility, tolerability, and clinical benefit of an exclusively ambulatory regimen for high-risk, elderly patients with advanced MF which warrants further evaluation in a prospective clinical trial.

Observation on the Clinical Effect of Applying Vinaclat Combined with Demethylation Drug Therapy in Patients with Acute Myeloid Leukemia

Objective: To investigate the therapeutic effect of applying venetoclax combined with demethylating drugs in treating patients with acute myeloid leukemia (AML). Methods: Eighty cases of AML patients treated with venetoclax combined with demethylating drugs in our hospital were selected from March 2021 to March 2024, including 40 cases of primary treatment patients and 40 cases of relapsed and refractory patients. The efficacy and safety of the combined drug therapy was analyzed. Results: The primary treatment group was presented with a complete remission (CR) rate of 40.5%, partial remission (PR) rate of 47.50%, no response (NR) rate of 12.50%, and a remission rate of 87.50%. The relapsed- refractory group was presented with a CR rate of 37.50%, PR rate of 42.50%, NR rate of 17.50%, and a remission rate of 87.50%. There was no statistical significance between the groups (P &gt; 0.05). The hematological adverse reactions of the combined treatment for AML were leukopenia and the non-hematological adverse reactions were mainly infections, with an incidence rate of 87.50%. Conclusion: The efficacy of venetoclax combined with demethylating drugs in AML was remarkable and the treatment regimen can be adjusted according to the treatment-resistant response.

Allogeneic Stem Cell Transplantation in Refractory Acute Myeloid Leukaemia.

Refractory acute myeloid leukaemia is very difficult to treat and represents an unmet clinical need. In recent years, new drugs and combinations of drugs have been tested in this category, with encouraging results. However, all treated patients relapsed and died from the disease. The only curative option is allogeneic transplantation through a graft from a healthy donor immune system. Using myeloablative conditioning regimens, the median overall survival regimens is 19%. Several so-called sequential induction chemotherapies followed by allogeneic transplantation conditioned by reduced intensity regimens have been developed, improving the overall survival to 25-57%. In the allogeneic transplantation field, continuous improvements in practices, particularly regarding graft versus host disease prevention, infection prevention, and treatment, have allowed us to observe improvements in survival rates. This is true mainly for patients in complete remission before transplantation and less so for refractory patients. However, full myeloablative regimens are toxic and carry a high risk of treatment-related mortality. In this review, we describe the results obtained with the different modalities used in more recent retrospective and prospective studies. Based on these findings, we speculate how allogeneic stem cell transplantation could be modified to maximise its therapeutic effect on refractory acute myeloid leukaemia.

Clinical Characteristics, Investigations and Treatment in Children with Chronic Urticaria: An Observational Study

Background and Objectives: The guidelines for chronic urticaria in children contain recommendations that are often based on adult studies. The diagnostic pathway has not been standardized and the effectiveness of anti-H1, omalizumab, montelukast, and systemic glucocorticoids is rarely reported in the pediatric population. There is a wide variation in the rate of remission of chronic urticaria between studies. The aim of this study is to enhance our understanding of pediatric chronic urticaria. Materials and Methods: This study enrolled 37 children with chronic urticaria aged from 0 to 18 years. Demographic parameters, medical history, clinical features, laboratory data and treatment information were collected. Children were treated with the recommended dosage of second-generation H1-antihistamines, which was increased by up to twofold. Omalizumab was added for refractory anti-H1 patients. A three-day course with systemic glucocorticoids was administered for severe exacerbations. Montelukast was administered to some children. Results: Wheals without angioedema were common. Chronic urticaria was spontaneous in 32 children (86.48%), inducible in 2 (5.41%), induced by a parasite in 1 and vasculitic in 2. Treatment of the potential causes of chronic urticaria was of no benefit, except for eradication of Dientamoeba fragilis. Chronic urticaria was resolved within three years in 45.9% of cases. Allergic diseases were present in nine children (24.32%) and autoimmune diseases were present in three (8.11%). All children were treated with anti-H1 at the licensed dose or at a higher dose. A partial or complete response to anti-H1 was observed in 29 (78.38%) patients. Montelukast showed no benefit. All children treated with omalizumab responded. Systemic glucocorticoids were successfully used to treat exacerbations. Conclusions: Our findings indicate that laboratory tests should not be routinely performed in children with chronic urticaria without clinical suspicion. However, comorbidities such as thyroid autoimmune disease and coeliac disease are suggested to be monitored over the chronic urticaria course. These clinical conditions could be diagnosed from the diagnostic framework of chronic urticaria. Increasing the dosage of anti-H1 and omalizumab was effective in children resistant to standard treatment but we still need further studies to generate a standard patient-centered treatment.

FAT1 weighted MRI: Diffusion meets anatomical imaging and application in thalamic surgery for tremor

Abstract Patient-specific targeting of the Ventral intermediate nucleus (Vim) of the thalamus can be achieved with MR connectivity. Nevertheless, there are several drawbacks to using tractography-based targeting methods to visualise distinct thalamic nuclei (e.g., subjective region of interest selection, and thresholding of resulting tracts and clusters). Fractional anisotropy (FA) mapping, another product of diffusion MRI (dMRI), does not rely on tractography, and could thus be clinically more viable for discerning thalamic anatomy for stereotactic surgery. The aim of this study is to develop and present a hybrid, high-resolution, and high-fidelity imaging modality that combines contrast from FA maps as well as anatomical T1 sequences (FAT1 imaging); and to evaluate FAT1 based Vim-target definition. Imaging and outcome data of 35 consecutive refractory tremor patients who had undergone 43 connectivity guided deep brain stimulation (DBS) and/or radiofrequency thermocoagulation (RF-T) between 2013 and 2021 were included. First, the pre-operatively acquired dMRI and MPRAGE sequences were used to create FAT1 maps in retrospect. Then, an FAT1 based Vim-target was planned by an experienced functional neurosurgeon who was blinded for patient outcome. Finally, to investigate FAT1 based targeting, a post-hoc analysis was carried out of the degree of overlap between the newly created FAT1 based Vim-target, and the volume of tissue activation (VTA, in case of DBS) or lesion volume (in case of RF-T). This degree of overlap was compared between favourable and unfavourable outcome groups: outcomes were measured by experts blinded for imaging data at the last follow-up using a Clinical Global Impression-Improvement score (CGI-I), where a CGI-I score of 1-2 (i.e., FTMTRS improvement of ≥50%) was considered favourable. In 36 of the 43 (84%) performed surgeries (24 DBS and 19 RF-T), FAT1 based Vim-targeting was possible. For the group showing favourable outcome (71% of the patients at a median follow-up of 13 months), the mean amount of overlap between the FAT1 based Vim-target and the VTA or lesion was 42% (±13), versus 17% (±15) for patients with an unfavourable outcome (MD 25%, 95% CI 14–35, p &amp;lt; 0.0001). Retrospective use of FAT1 based Vim-targeting as a tool to predict outcome had a sensitivity of 90%, specificity of 80%, positive predictive value of 90%, and negative predictive value of 80%. In conclusion, FAT1 imaging is a new, high-resolution, and high-fidelity modality that combines diffusion and anatomical MRI. It provides a fast and efficacious way of targeting the ventral intermediate nucleus of the thalamus. In this study, FAT1 based targeting was highly accurate in predicting outcomes after deep brain stimulation and radiofrequency thalamotomy.

Antiphospholipid Patients Admitted in the Intensive Care Unit: What Must The Rheumatologist Know?

Antiphospholipid syndrome (APS) is a rare systemic autoimmune disorder that can escalate into a 'thrombotic storm' called the catastrophic antiphospholipid syndrome (CAPS), frequently requiring ICU admission for multiple organ failure. This review aims to offer insight and recent evidence on critically-ill APS patients. The CAPS classification criteria define this condition as the involvement of at least three organs/systems/tissues within less than a week, caused by small vessel thrombosis, in patients with elevated antiphospholipid antibodies levels. These criteria do not encompass the full spectrum of critically-ill thrombotic APS patients and they need to be cautiously used for the bedside diagnosis of CAPS. Thrombocytopenia is the laboratory hallmark of CAPS, sometimes dropping below 20G/L, but a complete thrombotic microangiopathy pattern is infrequent. Anticoagulation is the pivotal treatment for APS and CAPS, associated with improved outcome. Triple therapy - the combination of anticoagulation, high-dose corticosteroids, and either plasma exchange or intravenous immunoglobulins - remains the standard treatment for CAPS patients. Eculizumab, an anti-C5 monoclonal antibody, may be useful in refractory patients. Despite significant progress, CAPS mortality rate remains high. Its diagnosis and management are complex, requiring a close multidisciplinary cross talk between APS specialists and intensivists.

Impact of prior lenalidomide or proteasome inhibitor exposure on the effectiveness of ixazomib-lenalidomide-dexamethasone for relapsed/refractory multiple myeloma: A pooled analysis from the INSURE study.

To characterize the impact of prior exposure and refractoriness to lenalidomide or proteasome inhibitors (PIs) on the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma (RRMM). INSURE is a pooled analysis of adult RRMM patients who had received IRd in ≥2 line of therapy from three studies: INSIGHT MM, UVEA-IXA, and REMIX. Overall, 391/100/68 were lenalidomide-naïve/-exposed/-refractory and 37/411/110 were PI-naïve/-exposed/-refractory. Median duration of therapy (DOT) was 15.3/15.6/4.7 months and median progression-free survival (PFS) was 21.6/25.8/5.6 months in lenalidomide-naïve/exposed/refractory patients. Median DOT and PFS in PI-naïve/exposed/refractory patients were 20.4/15.2/6.9 months and not reached/19.8/11.4 months, respectively. The proportion of lenalidomide-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to adverse events (AEs) was ixazomib, 31.6/28.2/28.0% and 18.6/6.7/10.5%; lenalidomide, 21.9/28.2/16.0% and 16.1/6.7/10.5%; dexamethasone, 18.4/20.5/16.0% and 10.6/0/10.5%, respectively. The proportion of PI-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to AEs was: ixazomib, 44.4/28.8/27.8% and 22.2/16.7/15.7%; lenalidomide, 33.3/22.0/19.4% and 16.7/15.9/11.8%; dexamethasone, 33.3/17.4/16.7% and 16.7/9.5/7.8%, respectively. REMIX AE discontinuation rates were unavailable. IRd appeared to be effective in RRMM patients in routine clinical practice regardless of prior lenalidomide or PI exposure, with better outcomes seen in lenalidomide- and/or PI-nonrefractory versus refractory patients.

B-cell immune dysregulation with low soluble CD22 levels in refractory seronegative myasthenia gravis.

Myasthenia gravis (MG), primarily caused by acetylcholine receptor (AChR) autoantibodies, is a chronic autoimmune disorder causing severe muscle weakness and fatigability. In particular, seronegative MG constitutes 10%-15% of MG cases and presents diagnostic challenges especially in early-onset female patients who often show severe disease and resistance to immunosuppressive therapy. Furthermore, the immunopathology of seronegative MG remains unclear. Thus, in this study, we aimed to elucidate the pathogenic mechanism of seronegative MG using scRNA-seq analysis and plasma proteome analysis; in particular, we investigated the relationship between immune dysregulation status and disease severity in refractory seronegative MG. Employing single-cell RNA-sequencing and plasma proteome analyses, we analyzed peripheral blood samples from 30 women divided into three groups: 10 healthy controls, 10 early-onset AChR-positive MG, and 10 refractory early-onset seronegative MG patients, both before and after intravenous immunoglobulin treatment. The disease severity was evaluated using the MG-Activities of Daily Living (ADL), MG composite (MGC), and revised 15-item MG-Quality of Life (QOL) scales. We observed numerical abnormalities in multiple immune cells, particularly B cells, in patients with refractory seronegative MG, correlating with disease activity. Notably, severe MG cases had fewer regulatory T cells without functional abnormalities. Memory B cells were found to be enriched in peripheral blood cells compared with naïve B cells. Moreover, plasma proteome analysis indicated significantly lower plasma protein levels of soluble CD22, expressed in the lineage of B-cell maturation (including mature B cells and memory B cells), in refractory seronegative MG patients than in healthy donors or patients with AChR-positive MG. Soluble CD22 levels were correlated with disease severity, B-cell frequency, and RNA expression levels of CD22. In summary, this study elucidates the immunopathology of refractory seronegative MG, highlighting immune disorders centered on B cells and diminished soluble CD22 levels. These insights pave the way for novel MG treatment strategies focused on B-cell biology.

Treatment of chronic post-radiation cystitis with trans-urethral amniotic bladder therapy appears durable at 9 months: A clinical study.

Chronic radiation cystitis (CRC) develops after radiation therapy and can present with symptoms like urinary frequency, urgency, pelvic pain, and nocturia. We have previously reported that amniotic bladder therapy (ABT) provides symptomatic improvement in refractory CRC patients for up to 3 months. Herein, we evaluated the durability of ABT up to 6 months. CRC patients recalcitrant to previous treatments received ABT comprised of intra-detrusor injections of 100 mg micronized AM diluted in 10 mL 0.9% preservative-free sodium chloride. Clinical evaluation and questionnaires (Interstitial Cystitis Symptom Index (ICSI), Interstitial Cystitis Problem Index (ICPI), Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS), Overactive Bladder (OAB) Assessment Tool, SF-12 Health Survey) were repeated at pre-op and 2, 4, 8, 12, 16, 20, 24, and 36 weeks post-injection. Five consecutive patients with a mean age of 64.4 ± 20.1 years with a median CRC duration of 10 years were included and followed for 6 months. After ABT, the lower urinary tract symptoms improved as early as 2 weeks and were maintained up to 20 weeks. BPIC significantly improved from 36.6 ± 1.1 at baseline to 12.6 ± 1.5 at 16 weeks and 13.8 ± 2.9 at 20 weeks. At 24 and 36 weeks, the improvement was maintained in four (80%) of the five patients (BPIC = 13.8 ± 1.0). Uroflow assessment showed voiding volume improved two-fold in four of the five patients at 24 weeks compared to baseline. Our data suggest that a significant number of CRC patients may have durable benefit after ABT. Despite this, some of them can show symptoms rebound at 24 weeks.

Endovascular Treatment for Cerebral Venous Sinus Thrombosis: Comparison among Different Endovascular Procedures

Abstract Background: Cerebral venous sinus thrombosis (CVST) is a rare, treatable cause of stroke. Even though CVST has an established medical treatment, 15% of patients remain refractory to treatment. These patients may be candidates for endovascular treatment (EVT), yet the selection of patients remains a challenge. The study aims to understand the profile and outcome of patients treated with EVT and the type of procedure associated with good outcomes. Methods: This is a single-center, retrospective analysis of CVST patients who underwent EVT from 2009 till 2022. Patients who received only medical management were excluded. Modified Rankin Scale (mRS) ≤2 at 3 months was taken as the primary outcome. Secondary outcomes assessed were hospital stay, death, recurrence, mRS ≤ 2 at discharge, and angiographic recanalization. Results: Fifty-two patients were included. Twenty-eight (53.8%) were males; the mean age was 33.3 ± 12.3 years. Headache (n = 44, 84.6%) predominated among the symptoms. The common risk factors were anemia (n = 13, 25.5%) and hyperhomocysteinemia (n = 13, 25.5%). Worsening of sensorium (n = 21, 40.3%) and non-improvement of symptoms (n = 15, 28.8%) were the common indications for the procedure. Twenty-five (48.1%) people underwent in situ thrombolysis (IST). Death occurred in eight (15.3%) patients. Thirty-six (73.5%; 36/49) patients had a good outcome at 3 months. IST had a significantly better outcome (mRS ≤ 2, n = 20, 80%) compared to other procedures (P = 0.04). Hospital stay was lesser in the IST subgroup, but without statistical significance. Midline shift &gt;5 mm (odds ratio [OR] 6.8 [1.5–30.9], P = 0.01) and Glasgow Coma Scale &lt;9 before the procedure (OR 27.2 [3.1–236.4], P = 0.002) predicted bad outcomes at 3 months. Female gender (OR 4.5 [1.07–8.8], P = 0.03), presence of altered sensorium (OR 10.2 [1.2–87.5], P = 0.01), encephalopathic syndrome (P = 0.02), presence of parenchymal bleed (OR 3.7 [0.9–4.5], P = 0.04), and midline shift (OR 4.8 [1.1–20.2], P = 0.03) were associated with poor outcome at discharge. Conclusion: EVT yielded good outcomes in carefully selected, medically refractory patients of CVST. IST performed well compared to other procedures.

Organ donation after extracorporeal cardiopulmonary resuscitation for refractory out-of-hospital cardiac arrest in a metropolitan cardiac arrest centre in Milan, Italy

IntroductionExtracorporeal cardiopulmonary resuscitation (ECPR) may improve survival in refractory out-of-hospital cardiac arrest (OHCA) but also expand the donor pool as these patients often become eligible for organ donation. Our aim is to describe the impact of organ donation in OHCA patients treated with ECPR in a high-volume cardiac arrest centre. MethodsRate of organ donation (primary outcome), organs harvested, a composite of patient survival with favourable neurological outcome or donation of ≥ 1 solid organ (ECPR benefit), and the potential total number of individuals benefiting from ECPR (survivors with favourable neurological outcome and potential recipients of one solid organ) were analysed among all-rhythms refractory OHCA patients treated with ECPR between January 2013–November 2022 at San Raffaele Hospital in Milan, Italy. ResultsAmong 307 adults with refractory OHCA treated with ECPR (95% witnessed, 66% shockable, low-flow 70 [IQR 58–81] minutes), 256 (83%) died during hospital stay, 33% from brain death. Donation of at least one solid organ occurred in 58 (19%) patients, 53 (17%) after determination of brain death and 5 (1.6%) after determination of circulatory death, contributing a total of 167 solid organs (3.0 [IQR 2.5-4.0] organs/donor). Overall, 196 individuals (29 survivors with favourable neurological outcome and 167 potential recipients of 1 solid organ) possibly benefited from ECPR. ECPR benefit composite outcome was achieved in 87 (28%) patients. Solid organ donation decreased from 19% to 16% in patients with low-flow < 60 minutes and to 11% with low-flow < 60 minutes and initial shockable rhythm. ConclusionsWhen ECPR fails in patients with refractory OHCA, organ donation after brain or circulatory death can help a significant number of patients awaiting transplantation, enhancing the overall benefit of ECPR. ECPR selection criteria may affect the number of potential organ donors.

Ustekinumab or Vedolizumab after Failure of Anti-TNF Agents in Crohn’s Disease: A Review of Comparative Effectiveness Studies

Background: Anti-tumour necrosis factor (TNF) agents are effective in Crohn’s disease (CD), but some patients lose responsiveness and require alternative biologic therapy. Until recently, ustekinumab and vedolizumab were the only other biological agents approved for use in CD. There are no randomised trials which compare the efficacy of these two agents in patients with anti-TNF refractory disease, but several retrospective cohort studies have compared their effectiveness in this setting. Aim: To review the effectiveness of ustekinumab and vedolizumab in anti-TNF refractory patients with CD. Methods: We included studies that compared the effectiveness of ustekinumab and vedolizumab in treating patients with anti-TNF refractory CD. We recorded the sample size, primary and secondary outcome measures and whether the studies employed adjustments for appropriate confounders. Results: Fourteen studies were included with a total sample size of 5651, of whom 2181 (38.6%) were treated with vedolizumab and the rest were treated with ustekinumab (61.4%). Of the fourteen studies included, eight found ustekinumab to be more effective in achieving clinical remission/steroid-free remission in the induction phase or during maintenance therapy (at least 1-year post-treatment) or that treatment persistence rates with ustekinumab were higher than with vedolizumab. Only one study reported vedolizumab to be superior during the maintenance phase in terms of clinical remission or treatment persistence rates. Biochemical outcomes were reported in five studies, two of which showed superiority for ustekinumab at 14 weeks and the other at 52 weeks. Only two studies reported endoscopic and/or radiologic outcomes; of these, one study showed ustekinumab to be significantly better at achieving endoscopic and radiologic responses. Adverse outcomes were broadly comparable, barring a single study which reported a lower hospitalisation rate for severe infection with ustekinumab. Conclusions: Most studies found ustekinumab to be more effective or non-inferior to vedolizumab in treating patients with anti-TNF refractory CD. Although many studies adjusted appropriately for confounders, the possibility of residual confounding remains and further data from prospective studies are warranted to confirm these findings. Further studies are required to compare these two therapies to other emerging therapies, such as Janus-kinase inhibitors.

Platelets retain function and can be stored following disruption of human leucocyte antigens.

Antibodies to human leucocyte antigen (HLA) Class-I antigens can lead to refractoriness to platelet transfusion. Although this can be overcome by transfusion of HLA-compatible platelets, they are not always available. Disruption of HLA antigens on platelets by acid treatment may be a suitable alternative when no other components are available. The aim of this study was to assess the effect of HLA disruption and subsequent storage of platelet components. Platelet components were treated with 0.9% saline or citric acid solution (pH 3.0), and then stored until expiry (Day 7). HLA and platelet glycoprotein expression, platelet viability, activation and sialylation were measured by flow cytometry. Release of soluble factors was measured by ELISA and metabolism by biochemistry analyser. Reactivity to patient anti-sera containing anti-HLA antibodies was measured using platelet immunofluorescence tests (PIFTs) and monoclonal antibody immobilization of platelet antigen (MAIPA) assays. Platelet function was measured using aggregometry and thromboelastography (TEG). Acid treatment reduced detection of HLA Class-I on platelets by 75%, with significant reductions in reactivity to patient anti-sera. Acid treatment reduced platelet content and viability, increased platelet activation and accelerated metabolism. Glycan cleavage was increased by acid treatment. Treatment reduced platelet activation following agonist stimulation by ADP and TRAP-6, but platelets remained functional, displaying increased aggregation response and reduced time to clot formation by TEG. Although HLA disruption had some detrimental effects, acid-treated platelets remained functional, retaining their capacity to respond to agonists and form clots, and with further development could be used to support refractory patients.

The Efficacy of Carfilzomib Treatment in Bortezomib-Refractory Patients-Real Life Experience in a Tertiary Romanian Hospital.

Background: Proteasome inhibitors (PIs) represent one of the most effective classes of therapy for patients with multiple myeloma (MM) and are incorporated in many of the current treatment regimens. The first-generation PI, bortezomib, has shown impressive results in patients with either newly diagnosed or relapsed/refractory MM, but once patients become resistant, treatment is increasingly challenging. Although the existing data show that the second-generation PI, carfilzomib, is highly efficient, there is still limited knowledge regarding the response to carfilzomib-based therapy in bortezomib-resistant patients. The aim of this study was to evaluate carfilzomib treatment performance in bortezomib-sensitive versus -refractory patients, in a real-life eastern European country setting. Methods: We retrospectively evaluated 127 adult patients exposed to bortezomib with relapsed or refractory MM, that subsequently received a carfilzomib-based therapy. We investigated the differences in the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) after carfilzomib-based therapy between the two patient groups. Results: The ORR in the bortezomib-sensitive group was significantly higher than that in the refractory group, leading to a superior PFS in this category of patients. For patients presenting with a high cytogenetic risk, we observed a significant difference in PFS between the bortezomib-sensitive and -refractory group, while standard cytogenetic risk patients presented a similar PFS regardless of the bortezomib sensitivity status. In addition, in patients with ISS (International Staging System) stage I or II, the previous sensitivity to bortezomib correlated with an improved PFS, while for patients with ISS stage III, both groups had a comparable PFS. No significant differences in OS were observed between the two groups. Conclusions: In countries where novel or experimental therapies are not readily available, carfilzomib-based therapy can still be a viable therapy option for patients presenting with bortezomib-refractory status, an ISS stage III, and standard cytogenetic risk.